N-Phenethyl trialkylmethanobenz-azolines

ABSTRACT

1,2,3,4,5,6-Hexahydro-3-( Beta -phenenthyl)-2,6,11-trialkyl-2,6methanobenzazocin-8-ols, analgetics.

mte States Pate 1 1 1111 3 091 050 Sallay 1 June 241-, 11975 N-PHENETHYL [56] References Cited TRIALKYLMETHANOBENZ-AZOLHNIES UNITED STATES PATENTS I Inventorr Stephen Sallay, Fort y 3,639,407 2 1972 Clarke at 111. 260/293.54 3,647.806 3/1972 Cross 260/293.54 [73] Assgnee' Pudue Research Foundaum West 3.700734 10/1972 Robinson et a] 260/293.54 Lafayette 3,764.606 10/1973 Akkerman et a1. 260/293.54 [22] Filed: Mar. 20, 11974 Primary E.\'aminer-G. Thomas Todd {211 Appl' No" 452852 Attorney, Agent, or FirmJames L. Rowe; Everet F.

Related US. Application Data Smith [63] Continuation-impart 0f Ser. No. 3921844, Aug. 29,

1973. 57 ABSTRACT 152 US. Cl. 260/293.54; 424/267; 260/DIG. 13 112131415,6'HeXahYdY'3-(#PheY'emhYU-ZQ11' 51 1m. (:1 C07d 39/00 trialkyl-z-@mthanobeZaZOCiMQlS, analgetics- [58] Field of Search 260/293.54, DIG. l3

3 Cllaims, N0 Drawings N-PHENETHYL TRIALIKYLMETHANOBENZ-AZOLINES CROSS-REFERENCE This application is a continuation-in-part of my copending application Ser. No. 329,844, filed Aug. 29, 1973.

BACKGROUND OF THE INVENTION May and Murphy, J. Org. Chem., 20, 157 1955) first achieved the synthesis of benzazocines (benzomorphans). (Y and P CH X, Z, and Q H in formula XX below.) The tricyclic system can be regarded as a simplified morphine structure.

The compound had about one-half the analgesic activity of meperidine or of dromoran. In a continuation of this research program, May, J. Org. Chem., 21, 899 (1956) prepared an N-phenylethyl analog (Y CH P CH CH C H X, and Z, and Q H in formula XX), yielding a compound with about one-third the analgesic activity of the correspondingN-methyl compound. In a further extension of this work, May and Fry, J. Org. Chem, 22, i366 (1957) prepared compounds with a methyl group present on the endomethylene bridge (Y, Z, and P CH X and Q H in formula XX). The corresponding S-hydroxy compound (Y, Z, and P CH X OH, Q H in formula XX) was also prepared, and this latter compound was a potent analgesic with a relatively low toxicity. Eddy, Murphy and May disclosed a novel synthesis for compounds corresponding to XX wherein Y andPare CH Q is H and X is permissibly hydroxy, in J Org." Chem., 22, I370 (I957). Finally, May and Eddy in J. Org. Chem, 24, 294 (.1959) described two novel analgesic compounds in which, in

formula XX,X OH,Y and Z CH Q H and P is either methyl or phenethyl. The compound in which P was methyl was resolved into d and l isomers with the levo isomer, having an'ED of 1.7 mgl/kg. The corresponding phenethyl derivatives (P CH CH C H on being resolved yielded a levo isomer and a dextro isomer both of which were analgesically active, the levo isomer being times more potent than morphine. The dextro isomer had an ED 6.7 mg/kg and manifested a low physical dependence. This lattercompound is now a marketed analgesic with the generic name pheently lost in an interference between that patent and U.S..Pat. No. 3,138,603. Other Gordon patentsinclude U.S. Pat. No. 2,924,603 which covers compounds of formula XX above wherein X OH, Y and Z CH eluding hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid and the in U.S. Pat. No. 2,959,594 but the claims were appar- Q H and P is aheterocyclic ethyl group such as pyridylethyl, thienylethyl, etc. and U.S. Pat. No. 3,033,867 in which nicotinyl esters of the compounds claimed by May in U.S. Pat. No. 3,138,603 are described. Archer, U.S. Pat. No. 3,250,678, claims compounds according to formula XX above in which one of Y and Z is ethyl, the other being hydrogen, methyl or ethyl, X OH, O H and P lower alkenyl containing 3-6 carbon atoms, particularly ally] and 3-methyl- Z-butenyl. The patent also covers the marketed compound pentazocine in which X OH, Y and Z CH;,, O H, and P 3methyl-2-butenyl. A second Archer patent, U.S. Pat. No. 3,372,l65, covers related compounds in which a cyclopropylmethyl side chain replaces the 3-methyl-2-butenyl of pentazocine (XX above wherein X OH, Y and Z CH Q =H, and P cyclopropylmethyl).

None of the cited literature discloses a single compound in which Q in formula XX is other than hydrogen. Furthermore, none of the syntheses described in the cited literature provides a synthetic procedure for the preparation of such a compound; in other words, the known synthetic procedures rely upon the absence during the ring closure reaction of any substituent group at the position to be occupied by Q in the benzazocine ring system before it is formed. Furthermore, there is no procedure known in the literature by which a substituent in Q-position could be introduced after the benzazocine ringsystem is completed.

It is an object of this invention to provide 2 alkylbenzazocines active as analgesic substances and as analgesic antagonists.

SUMMARY OF THE INVENTION This invention provides benzazocines of the following formula:

wherein each alk independently is C -C alkyl and R' is H or alk. Also included within the scope of this invention are the pharmaceutically-acceptable acid addition salts of the bases represented by the above formula formed with non-toxic acids. These acid addition salts include salts derived from non-toxic inorganic acids inlike, as well as salts of non-toxic organic acids including acetic acid, maleic acid, fumaric acid, malic acid, succinic acid, tartaric acid, citric acid, benzoic acid, 2,4-

dinitrobenzoic acid, p-chlorobenzoic acid, naphthoic acid, p-toluenesulfonic acid, methanesulfonic acid and i i The compounds of this invention are solids, and are usuallyisolated and purified in the form of an acidaddition salt. Thecompounds are prepared by a multistep procedure whereby the tricyclic benzazocine ring structure containing the desired 2-alkyl substituents is built up from a tetralone to yield a compound of the above formula wherein R is H. The active analgctics and analgctic antagonists of this invention are prepared therefrom by standard alkylation procedures.

The more roundabout procedure must be employed since direct alkylation of III provides a 3,3-dialkyl tetralonc derivative.

Ozonolysis of the l-allyl group of the Z-tctralone The compounds of this invention (l) are optically ac- 5 (VI) followed by reductive cleavage of the ozonide tive in that each contains three asymmetric carbon quantitatively produces the tetralin y-keto aldehyde atoms at positions 2, 6 and 11 of the benzazocine ring, (Vlll). Treatment of the keto aldehyde with a trace of (see formula XX for numbering) yielding theoretically alkali causes an intramolecular aldol condensation to 8 diastereoisomers. Howeven since the methano bridge take place, thus producing the tricyclic tetrahydro-5,8- can only be cis fused. one-half of the theoretical numl0 mCth11nO-5-fi-bcnzocyclohcplcn'IOQnCJ'OI dcrivu' ber of isomers are eliminated, leaving two pairs of diafive I r /1 Q i 2 i f OH re d O CO i 0' a 4 es a l i CH' CHO L15 0 a l VIII IX stereoisomers occurring as two racemates, the a-dl or Th benzucyclohcptenolone X represents a di less Soluble racem'dte and the 3* or more Soluble reoisomeric pair with a cis and a trans hydroxyl at the cemate. Resolution of the racemate into its component C, Carbon (cis meaning th t th h droxyl i o th me d and I isomers can be accomplished by salt formation ide of h 7- b d in as the methano brid e and with an optically active acid and separation of the diatrans meaning that the hydroxyl is on the opposite side stereoisomeric salt, by procedures well known in the of the 7-membered ring from the methano bridge). art. Compound [X is the key intermediate for the produc- In synthesizing the compounds of the present inven' tion of compounds represented by formula I and the tion, a l-alkyl-7-alkoxy-2-tetralone (ll) prepared by first step in the transformation of the benzocyclohepthe procedure of Kuehne J. Am Chem, 3 83, tenolone (lX) to a compound offormula l is the protec- 1492-8 (1961) is alkylated with an allyl halide such as tion of e y y g p via ether formation. p the bromide or chloride to produce the corresponding erably y py y F The 1 1 1 1 1 7 z my dropyranyloxy compound (X) lS SUbJCCIGd to a Wittig T T i' t 1 Next the z'tetfalone is transformed to B ester reaction in which a triphenyl phosphonium-methylide y carbaikoxxlatlon Procedure g 3 dlalkyl Carbonin a solvent such as dimethylsulfoxide replaced the 10- ate such as dimet hylcarbonate or diethylcarbonate as keto group i a methylene group, i l i the exom. the carbalkoxylating agent. As added solvent such as ethylenebenzobicycloheptenyl ether (Xl) in quantitatetrahydrofurane may optional y be present. The tive yield. Removal ofthe 7-hydroxy group readily pro- B- 6516f thus p p can be alkylated us ng duces the exomethylene ketone (XVI). The yield for conventional procedures employed with other B-keto the six step procedure (Vl through XVI) is about esters to provide V which, after hydrolysis and spontapercent overall.

. 5O neous decarboxylation, yields a 3-alkyl-2-tetralone (Vl).

COO-d k COO-a l k f a i r1 d r\ l llaOE- p O a l l4 a l l i a I (C I, l I

base CO If higher C -alkylidene derivatives are desired, for example, the ethylidene or n-propylidene derivatives, the appropriate Wittig reagent is employed such as triphenyl phosphonium-ethylide of triphenyl phosphonium-n-propylide.

Next, the methylene linkage of XVI is reduced to yield either a cis C -C diakly diastereoisomer or a trans C C dialkyl diastereoisomer (XVII), depend ing on the reduction conditions employed. Reduction of the exomethylene ketone XVI with a platinum-om carbon catalyst yields predominantly the cis-C -C dialkyl diastercoisomer of 6,7,8,9-tetrahydro-5,8-dialkyl IO-methyI-B-alkoxy-S ,8-methano-( 5 I1)-benzocyclohepten-7-one. Reduction of the lO-ethylidene or propylidene derivatives yields the corresponding cislO-ethyl or cis-lO-propyl compound.

As an alternative procedure, the corresponding pure trans isomer is prepared by a stereoselective hydroboration-oxidation reaction on the exomethylene compound (XI) to form an equatorially-oriented hydromethyl (methylol) group. The methylol hydroxyl is next esterified with p-toluenesulfonyl chloride in pyridine. Hydride reduction of the tosylester followed by acid hydrolysis of the ethereal linkage and oxidation of the C -hydroxyl yields directly the trans-C 4: dialyl diastereoisomer of 6,7,8,9-tetrahydro-5,S-dialkyl-IO- methyl-3-alkoxy-5,8-methano-( 5 I-j )-benzocyclohepten-7-one (XVII). Higher C -alkyl derivatives having a trans configuration are prepared in similar fashion. Both the cis and trans-C,=,-C dialkyl derivatives are represented by XVII.

Next, the tricyclic ketone XVII of either cis or trans configuration is converted to the oxime with hydroxylamine. Because of the hindrance of the C -alkyl group, only the anti-oxime is formed. At the oxime stage the two C -diastereoisomers can be separated by crystallization. Beckmann rearrangement of each oxime proceeds readily to yield the lactam diastereoisomers (XIX).

XIX

Lithium aluminumhydride reduction of the lactam XIX yields directly the desired 8-alkoxy tricyclic secondary amine (XX) wherein P H, X R'O, and Y, Q, R and Z alk.

The 8-alkyl ether is then transformed to the corresponding hydroxy compound by treatment with pyridinium hydrochloride to yield the desired aminophenol starting material (I) wherein R and R H.

The above procedure can also be used to synthesize a benzazocine (XX) in which Y and Z CH and X OH and Q and P H. Alkylation of this particular derivative on the N yields, among other compounds, pentazocine. In preparing compounds in which Q is H (rather than alkyl as in applicants compound), the tetralone alkylation steps (IV VI) can be obviated and (III) can be ozonized directly to yield a 'y-keto aldehyde which undergoes an intramolecular condensation to give a methano-bridged compound.

The analgetic compounds of this invention are pre pared by alkylating the secondary amine (XX) with phenethylbromide or chloride. Preferably, however, the secondary amine is acylated with phenacetylchloride and the corresponding amide reduced with LiAlH, or the like to yield an N-phenethyl derivative.

This invention is further illustrated by the following specific examples.

EXAMPLE 1 3 ,4-Dihydrol -methyl- 1 -allyl7-methoxynaphthalen- 2( lfl)-one A solution of 57.0 g. l-methyl-7-methoxy-2-tetralone prepared by the method of M. E. Kuehne, J. Am. Chem.

S00, 83, 14928, 1961 in 50 ml. of dry tetrahydrofuran was slowly dropped into a suspension of 7.2 g. sodiumhydride in 200 ml. of dry tetrahydrofuran. The exothermic reaction was controlled by external cooling between 3545C. After the hydrogen evolution subsided, the solution was cooled to about +C. and treated with 37.4 g. allylbromide. The temperature of the reaction was kept between 30-40C. After the addition of the allylbromide had been completed, the reaction mixture was stirred for about 12 hours at room temperature. NaBr, produced in the above reaction was separated by filtration and the reaction mixture was evaporated to dryness. The residue was dissolved in ether, the ether solution extracted with water, dried and evaporated in vacuo to an orange-colored oil. The residual oil was distilled in vacuo to yield 64.5 g. 3,4- dihydro-l-methyl-1-allyl-7-methoXy-naphthalen- 2( lll )-one distilling in the range 119120C./,005 mm Hg. The IR spectrum exhibited bands at 3.27/J.(CH=CH2), 5.86p.( C=O) and 6.02;1.(HC=CH NMR (CDCl showed chemical shifts at 81.40 (s, 3H, C-CH 8 3.77 (s, 3H, OCH;,), and 8 5.20 (m, 3H, -CH=CH Following the above procedure, but substituting l-ethyl-7-methoxy-2-tetralone for l-methyl-7- methoxy-2-tetralone, one obtains 3,4-dihydro-1-ethyl- 1-allyl-7-methoxynaphthalen-2( l 1i)-one.

EXAMPLE 2 3,4-Dihydro-1-methyl-l-allyl-3-carbomethoxy-7- methoxy-naphthalen-2( lH )-one 62.0 g. of 3,4-dihydro-1-methyl-1-allyl-7- methoxynaphthalen-2-(1fl)-one prepared by the procedures of Example 1, was dropped into a suspension of 6.5 g. of sodium hydride in 250 ml. of dimethylcarbonate and the resulting mixture gently refluxed until hydrogen evolution had subsided. The reaction mixture was cooled, and diluted with ether. The ether layer was extracted with water, separated and dried. Distillation yielded 65.8 g. of 3,4-dihydro-l-methyl-l-a11yl-3- carbomethoxy-7-methoxy-naphthalen-2( lfl)-one boiling in the range 146-l49C./0.01 mm. Hg. )t 5.72p. (ester), 5.83 u(ketone); 6.0lp.( C=CCOOCH The product exhibited an intensive dark violet color with ferric chloride.

EXAMPLE 3 3 ,4-Dihydro- 1 -methyl- 1 -al1yl-3-carbethoxy-7-methoxy naphthalen-2( 1 1i)-one Following the above procedure but substituting diethylcarbonate for dimethylcarbonate there is obtained 3 ,4-dihydro-1 -methyl- 1 -allyl-3-carbethoxy-7- methoxy-naphthalen-2(1H)-0ne. B.p.=149152C./

m \ma,1 3.26p,(CH CH2), 5.73L(e5- ter); 5.85;;(ketone); 6.03p.( C=CCOOEt).

Following the above procedure but substituting 3,4- dihydro- 1 -ethyl- 1 -al1yl-7-methoxy-naphthalen-2- (lfl)-one for 3,4-dihydro-l-methyl-1-allyl-7-methoxynaphthalen-2(l ll)-one in molar equivalent amount there is obtained 3,4-dihydro-1-ethyl-l-allyl-3- carbomethoxy-7-methoxy-naphthalen-2( lfl)-one.

EXAMPLE 4 3 ,4-Dihydrol ,3-dimethyl1-allyl-3-carbomethoxy-7- methoxy-naphthalen-2( 1 l-1)-one Procedure A.

A solution of 56.5 g. of 3,4-dihydrol-methyl-1-a1lyl- 3-carbomethoxy-7-methoxy-naphthalen-2-( lfl)-one in about 50 ml. of tetrahydrofuran was slowly added to a stirred suspension of 4.7 g. sodium hydride in about 250 ml. tetrahydrofuran. The reaction temperature was kept between 2025C. After the hydrogen evolution had ceased, 42.0 g. methyliodide were added to the reaction mixture within a few minutes. The temperature was maintained between 3040C. After the exothermic reaction had subsided, the reaction mixture was stirred at room temperature overnight. Inorganic substances were filtered off, and the solvent was evaporated in vacuo. The resulting oily residue was dissolved in ether, and the ether solution extracted with water, dried, filtered and evaporated in vacuo. The residual orange-yellow oil was distilled. 3,4-dihydro-l ,3- dimethyl-1-allyl-3-carbomethoxy-7-methoxynaphthalen-2(l lj)-one prepared by the above procedure boiled in the range 150C./0.01 mm Hg. Yield=55.0 g. The 1R spectrum exhibited bands at 3.2,u( C= CH 5.77,u.(ester), 5.85u(ketone). Ferric chloride test was negative.

Procedure B.

12.8 g. of 3,4-dihydro-l-methyl-1-allyl-7-methoxynaphthalen-2( lfl)one was introduced into a suspension of 1.4 g. sodium hydride in about ml. of dimethylcarbonate. The resulting mixture was gently refluxed until the hydrogen evolution had subsided. The reaction mixture was cooled and directly treated with 16.0 g. methyliodide at a temperature between 2540C. Sodium iodide separated while the reaction mixture was stirred overnight at room temperature. Ether was added, the inorganic salt separated by filtration, and the filtrate evaporated to dryness. The oily residue was distilled to yield 3,4-dihydro-l,3-dimethyl-l-a1lyl-3- carbomethoxy-7-methoxy-naphthalen-2(1fi )one boiling at l50C./0.015 mm. and identical with the product obtained by Procedure A of this Example.

Following the above procedure but substituting ethyliodide in molar equivalent amount during the alkylation step for methyliodide there is obtained 3,4- dihydro-1-methyl-3-ethyl-1-allyl-3-carbomethoxy-7- methoxy-naphthalen-2( l 1-1)-one. B.P.=113114C./0.00l mm. Hg; A 5.75u(@OCH 5.88 C=O); NMR (CDCl;,) 6 1.l5(t, 3H), 83.68 (s, 3H), 83.80 (s, 3H), 65.0 (m, 3H).

3,4-Dihydro-l-methy1-3-propyl-l-al1yl-3- carbomethoxy-7-methoxynaphthalene-2 (1fl)-one was prepared in similar fashion and distilled at l42C./0.0l mm Hg; hmar fl- 5 p. (ketone), 6.05;. (CH=CH NMR (CDCl:;) exhibited chemical shifts at 83.68 (s,COOCH;;), 83.81 (s, OCH 55.03 (m, Cfi =Cl;l Mass srEetrum showed themlowing major fragmentations m/e 330 (M'), 314, 289, 287, 273, 257, 229 (base), 201, 173.

Analysis for C H O Cale; C, 72.70; H, 7.93%. Found; C, 72.99; H, 8.07%.

Following the above procedure, but substituting 3,4- dihydro- 1 -ethyll -allyl-3-carbomethoxy-7-methoxynaphthalen-2(l li)-one for 3,4-dihydro-l-methyl-lallyl-3-carbomethoxy-7-methoxy-naphthalen-2- (l l-l)-one, there is produced 3,4-dihydro-3-methyl-1- ethyl-1-a1lyl-3-carbomethoxy-7-methoxy-naphthalen- 2(1fl)-one and 3,4-dihydro-1,3diethyl-1-a1lyl-3- earbomethoxy-7-methoxynaphthalen-2(1lj)-one(V).

EXAMPLE 5 3,4-Dihydro-1,3-dimethyl-l-allyl-7-methoxynaphthalen-2( lfl)-one A solution of 59.0 g. of 3,4-dihydro-l,3-dimethyl-3- carbomethoxy-7-methoxy-naphthalen-2( lfl)-one in 450 ml. of KOH/methanol was refluxed for 1-5 hours. K CO deposited during the reaction and was removed by filtration. The methanolic filtrate was evaporated to dryness. The resulting oily residue was disolved in ether, and the ether solution washed with water, and dried. The dired ethereal solution was distilled in vacuo, and the fraction boiling in the range l31133C./0.06 mm Hg. collected, the yield was 45.1 g. of 3,4-dihydro-l ,3-dimethyl-1-allyl-7-methoxynaphthalen-2(lL-1 )-one; b.p. l21124C./0.001 mm Hg. (glc purity 91.5%); lt 3.23,u(-CH=CH 5.85[.l,( C=0), 6.02,u.(- CH=CH2); NMR (CDCl;;) exhibited chemical shifts at 81.05 (cl, 3H; J=7 cps), 81.43 (s, 3H), 83.78 (s, 3H), 85.10 (m, 3H).

Mass spectrum showed the following major fragment ions: m/e 244 (M'), 229, 203, 175 (base). Analysis for C H O 244.32 requires: C, 78.63; H, 8.23%. found: C, 78.41; H, 8.08%.

Following the above procedure, but substituting for 3 ,4-dihydro-l,3-dimethyl-1-allyl-3-carbomethoxy 7 methoxy-naphthalen-2-( 1 l- 1 )-one an appropriately substituted 3,4-dihydro-l ,3-dialkyll -allyl-3- carbomethoxy-7-methoxy-naphthalen 2(1fl)-one, there is produced 3,4-dihydro-l-methyl-3-ethyl-l allyl- 7-methoxy-naphthalen-2-(lfl)-one b.p. 118C./0.001 mm. Hg.; l 5.87 C=O); NMR (CDCl;,) 80.98 (t, 3H), 81.02 (t, 3H), 81.35 (s, 311), 81.43 (s, 3H), 83.80 (s, 3H), 85.20 (m, 3H).

Mass spectrum exhibited the following major fragmentions m/e 258 (M*), 217, 189 (base).

. dihydro-3-methyl-1-n-p ropyl-1-allyl-7-methoxynaphthalen-2( lfl)-one are prepared in similar fashion.

EXAMPLE 6 1,2,3 ,4-Tetrahydro-1 ,3-dimethyl-7-methoxy-2-oxol naphthalene-acetaldehyde thalene-acetaldehyde, was distilled l50l55C./0.01 mm. Hg.; yield (several runs) 86-94; A,,,,,,"" 3.63 1 (-Cfl0), 5.83 (aldehyde oxo), 5.88 (ketone). Mass spectrum exhibited the expected molecular ion m/e at fragment peaks occurred at m/e 204,203, 202, 175 and 161.

Following the above procedure, but substituting for 3 ,4-dihydro-l ,3-dimethyll -allyl-7-methoxynaphthalen-2( lfl)-one an appropriate 3,4-dihydro-1,3- dialkyl-1-allyl-7-methoxy-naphthalen-2( lfi)-one, there is produced l,2,3,4-tetrahydro-l-methyl-3-ethyl- 7-methoxy-2-oxo-1-naphthalene-acetaldehyde b.p. 125C./0.001 mmg. Hg.; lt 3.65 1. (C l l O), 5.80;; (-CHQ), 5.85 1. (C=O); NMR (CDCl 81.0 (t, 3H), 81.50 (s, 3H), 83.80 (s, 3H), 812.1 (m, 1H). Mass spectrum exhibited a molecular ion m/e at260 (M*) and the following major fragment ions: m/e 246, 218, 217,216,189,176,175,162 and 161 (base).

1,2,3,4-tetrahydro-1-ethyl-3-n-propyl-7-methoxy- 2-oxo-1-naphthalene-acetaldehydei 1,2,3,4-tetrahydro-3-methyl- 1-ethyl-7-methoxy-2-oxo-1-n aphthalene-acetaldehyde and 1,2,3 ,4-tetrahydro-l ,3-diethyl-7-methoxy-2-oxo-1- naphthalene-acetaldehyde can be prepared in similar fashion. 1

EXAMPLE 7 6,7,8,9-Tetrahydro-5 ,8-dimethyl-3-methoxy-5,8- methano-5 1i-benzocycloheptene-7-01-l0-one A solution of 28.6 g. of 1,2,3,4tetrahydro-1 ,3- dimethyl-7-methoxy-2-oxo- 1 -naphthaleneacetaldehyde in 400 mlfof methanol was treated with 200 ml. of 2% KOH-methanol. The reaction mixture was left at room temperature for 16 hours. The solvent was evaporated in vacuo, and the resulting residue was dissolved in ether. The ether extract was in turn extracted with 10% hydrochloric acid at 0C. and then with water. The ether solution was dried and evaporated to yield a residue comprising 6,7,8,9-tetrahydro- A solution of 28.8 g. of 3,4-dihydro-1,3-dimethyl-ladded in small batchesto the vigorously stirred reac tion mixture. The temperature was maintained in the action mixture was filtered, and the organic layer was twice extractedwith water and once with sodium bicarbonate solution thereby removing the. last trace of acetic acid. The organic layer was dried, filtered and evaporated to dryness. The residue, comprising 1,2,3; 4-tetrahydro-1.3-dimethyl-7-methoxy-2-oxo-l-naphrange 2030C. After the ozonide was cleaved, the rebenzocyclohepteneJ-ol-10-one; weight 27.6 g.; A 2.88,u(strong OH), 5.75p.(five-membered ketone). Following the above procedure, but substituting for 1,2,3,4-tetrahydro-1,3dimethyl-7-methoxy-2-oxo-1- naphthalene-acetaldehyde the appropriate 1,2,3,4- tetrahydro-l ,3-dialkyl-7-methoxy-2-oxo-1 -naphthalene-acetaldehyde, one obtains 6,7,8,9-tetrahydro-5- methyl-8-ethyl-3-meth0xy-5,8-rnethano-5H- benzocycloheptene-7-ol-10 -one; yield 96.5%; )t 2.80;.t(-OH), 5.75,u.(five-membered ketone).

Similarly, 6,7,8,9-tetrahydro-5-ethyl-8-n-propyl- 3-methoxy-5,S-methano-5fl-benzocyclohepteneJ-oll0-one; 6,7,8,9-tetrahydro-8-methyl-5-ethyl-3- methoxy-S,8-methano-5 11-benzocycloheptene-7-ollO-one, 6,7,8,9etetrahydro-5,8-diethyl-3-methoxy-5,8- methano-5fl-benzocyclohepteneJ-ol-lO-one and 6,7, 8,9-tetrahydro-5-methyl-8-n-propyl-3-methoxy-5,8-

methano-Sfl-benzocycloheptene-7-ol-1O-one can be synthesized from the appropriate starting material.

EXAMPLE 8 6,7,8,9-Tetrahydro-5,8-dimethyl-3-methoxy-7- (tetrahydro-2-pyranyloxy)-5,S-methano-SH-benzocy- 27.6 g. of

methoxyclohepten- 1 O-one 6,7,8,9-tetrahydro-5 ,8-dimethyl-3- 5,8-methano-5fl-benzocycloheptene-7-ol-lO-one were dissolved in about 50 ml. of dihydropyran. A few crystals of p-toluenesulfonic acid were added. The resulting exothermic reaction was controlled by a cooling bath, and the internal temperature was kept below 35C. After the exothermic reaction had subsided, the mixture was allowed to stand for another 4 hours at room temperature, and was then diluted with ether. The ether layer was separated and extracted by sodium bicarbonate solution, dried, filtered and evaporated to dryness, yielding as a residue the crude tetrahydropyranyl ether of 6,7,8,9-tetrahydro-5,8-dimethyl-3- mcthoxy-7-(tetrahydro-Z-pyranyloxy)-5,S-methano- Sfi-benzocycloheptemlOone; )t 5.7 ..t(sharp C=O), 9.209.60p.(acetal), no hydroxyl absorption; quantitative yield.

Following the above procedure, but substituting for 6,7,8,9-tetrahydro-5,8-dimethyl-3-methoxy-5,8 methano-Sfi-benzocycloheptene-7-ol-l0one the appropriate 6,7,8,9-tetrahydro- 5,8-dialkyl-3-methoxy-5,8-methano-5flbenzocycloheptene-7-ol-10-one, one obtains 6,78,9- tetrahydro-S-methyl-8-ethyl-3-methoxy-7-(tetrahydro- 2-pyranyloxy-5,8-methano-5fl-benzocycloheptenel-one, 6,7,8,9-tetrahydro--ethyl-8-methyl-3- methoxy-7-(tetrahydro-Z-pyranyloxy)-5,8-methano- Sfl-benzocycloheptene-IO-one, 6,7,8,9-tetrahydro- 5,8-diethyl-3-methoxy-7-(tetrahydro-2-pyranyloxy)- 5,8methano-Sfl-benzocycloheptene-lO-one, 6,7,8,9- tetrahydro-5-methyl-8-propyl-3-methoxy-7- (tetrahydro- 2-pyranyloxy)-5,8-methano-5t1 -7-(tetrahydro-2- pyranyloxy)- 5,8-methano-Sfl-benzocyclohexene-l O-one ect.

EXAMPLE 9 6,7,8 ,9-Tetrahydro-5 ,8-dimethyl-3-methoxy-7- (tetrahydro- 2-pyranyloxy)- l O-methylene-S ,8-methano-51 -1 benzocycloheptene Eighty-one and six-tenths grams of triphenylmethylphosphonium bromide were introduced into a solution of dimsylsodium within minutes. The dimsylsodium was prepared from 5.5 g. of sodium hydride and 500 ml. of dry dimethylsulfoxide. The reaction temperature was kept between 1823C. under a nitrogen blanket. The yellow colored triphenylphosphoniummethylide thus produced was stirred at room temperature for an additional hour and then treated with a solution of 50.3 g. of 6,7,8,9-tetrahydro-5,8-dimethyl-3-methoxy-7- (tetrahydro-Z-pyranyloxy)-5,8-methano-5fi-benzocycloheptene-lO-one in 100 ml. of dimethylsulfoxide. The addition took about 10 minutes, and the moderately exothermic reaction was kept at a temperature in the range 24-35C. The dark brown reaction mixture was stirred for an additional hour between 4050C. and stored at room temperature overnight. The mixture was then poured onto an ice-water mixture and thoroughly extracted with hexane. Triphenylphosphoniumoxide formed as a by-product in the reaction was insoluble in both water and aliphatic hydrocarbons and was separated by filtration. The dried organic filtrate was evaporated to dryness in vacuo leaving a residual yellow gum comprising 6,7,8,9-tetrahydro-5,8- dimethyl-3-methoxy-7-(tetrahydro-Z-pyranyloxy)-l0- methylene-S,8-methanoiii-benzocycloheptene. The compound was obtained in practically quantitative yield. Spectrocopic evidence indicated a high level of purity, and thus the product was used in the succeeding and EXAMPLE l0 6,7,8,9-Tetrahydro-5 ,8-dimethyl-3-methoxylO-methylene-S,8-mcthano 5fl-benzocycloheptene-7-ol A solution of 28.1 g. of 6,7.8,9-tetrahydro-5,8- dimethyl-3-methoxy-7-(tetrahydro-2-pyranyloxy)-l0- methylene- 5,8-methano-5fl-benzocycloheptene in 300 ml. of 5% ethanolic oxalic acid containing 10 ml. of water was refluxed for 5 hours. The evaporated reaction mixture was dissolved in benzene, and the benzene solution extracted with dilute aqueous sodium hydroxide and water. The benzene solution was separated and dried. Evaporation in vacuo yielded residue of 21.0 g.

of an orange-colored gum comprising 6,7,8,9- tetrahydro-S,8dimethyl-3-methoxy-10-methylene-5,8- methano-5 1- l-benzocycloheptene-7-ol; k

Following the above procedure, but substituting for 6,7,8,9-tetrahydro-5,8-dimethyl-3-methoxy-7- (tetrahydro-Z-pyranyloxy)-l0-methylene-5,8- methano5fl-benzocycloheptene an appropriate 6,7,8,- 9-tetrahydro-5,8-dialkyl-3-methoxy-7-(tetrahydro-Z- pyranyloxy)-10-methylene-S,S-methano-Sflbenzocycloheptene, one can obtain 6,7,8,9-tetrahydro- 5-methyl-8-ethyl-3-methoxy10-methylene-5.8- methano-Sfl-benzocyclohepteneJ-ol b.p.=131C./0.004 mm. Hg.; A 2.80, 2.90p.(OH), 6.05}L( C=CH2); NMR, (CDCI 81.03 (t, 3H), 81.48 (s, 3H), 53.77 (s, 3H), 84.77 and 4.80 (two singlets for C= 1i Mass spectrum shows the M -ion m/e at 258 and fragment ions at m/e 243, 226, 225, 214, 211, 199 and (base).

Analysis for C H 0 258.35 requires: C, 79.03; H, 8.50%. found: C, 78.93; H, 8.86%.

6,7,8,9-Tet1'ahydro-5-ethyl-8-n-propyl-3-methoxylO-methylene-S,8-methano-5lj-benzocycloheptene-7- ol, 6,7,8,9- tetrahy- -5methyl-8-n-propryl-3-methoxy-10-methylene-5,8- methano-Sfl-benzocycloheptene-7-ol, 6,7,8,9- tetrahydro-8-methyl-5-ethyl- 3-meth0xy-lO-methylene-S,8-methano-5fl-benzocycloheptene-7-ol and 6,7,8,9-tetrahydro5,8-diethyl-3- methoxyl O-methylene-S ,S-methano-Sfl-benzocyc1oheptene-7-ol can be prepared in similar fashion.

EXAMPLE ll 6,7,8,9-Tetrahydro-5,8dimethyl-3-methoxy-10- methylene 5,8-methano-5H -benzocycloheptene-7-one A solution of 28.3 g. of 6,7,8,9-tetrahydro-5,8- dimethyl-3-methoxyl O-methylene-S,8-methano-5-H- benzocycloheptene-7-ol in 50 ml. pyridine was slowly introduced into a slurry of 23.0 g. of CrO in 300 ml. pyridine. The reaction mixture was stirred at room temperature for about 16 hours and was then diluted with ether. Inorganic material was separated by filtration. The filtrate was evaporated to a dark syrup which was extracted with ether. The ethereal extract was washed with dilute hydrochloric acid and water and was then dried. Evaporation of the solvent in vacuo yielded crude 6,7,8,9-tetrahydro-5,8-dimethyl-3-methoxy-10- methylene5,8-methano-Sfi-benzocycloheptane-7-one in quantitative yield, which crystallized upon standing. After recrystallization from ethanol-hexane, the compound melted at 8485.5C. x f s 5.75,u( C=), 6.0;1.(C=CHz); NMR (CDCl,,) 81.29 (s, 3H), 81.79 (s, 3H), 82.44 (s, 1H), 8 2.49 (s, 1H), 82.90 (s, 1H), 82.95 (s, 1H), 83.77 (s, 3H), 84.91 (s, 1H), 85.01 (s, 1H).

Mass spectrum exhibited the following major fragment ions: m/e 242 (M*), 227, 200, 199 and 185 (base).

Analysis for C H O 242.30 requires: C, 79.31; H, 7.49%. found: C, 79.10; H, 7.55%

The last six steps Examples -1 1 produced an overall yield of 80.7% of the desired product.

Following the above procedure but substituting for 6,7,8,9-tetrahydro-5 ,8-dimethyl-3-methoxyl 0- methylene-S,S-methano-Sfl-enzocyclohepteneJ-ol an appropriate 6,7,8,9-tetrahydro5,8-dialkyl-3-methoxy- -methylene-S,8-methano-5fl-benzocycloheptene-7- 01, one can obtain 6,7,8,9-tetrahydro-5-methyl-8-ethyl- 3-methoxy-10-methylene-S,8-methano5 11-benzocycloheptene7-one; m.p.=l03lO4C.; )\,,,,,,""'a= 5.75 u.(five-membered ketone), 6.O3p.( C=CH NMR (CDCI 0.86 (t, 3H), 81.70 (s, 3H), 83.75 (s, 3H), 84.90 (s, 1H), 85.10 (s, 1H).

Mass spectrum showed the following major fragment ions: m/e 256 (M 241,203, 199, and 185 (base).

Analysis for C H O 2,6.33 requires: C, 79.6,; H, 7.86%. found: C, 79.53; H, 7.64%.

6,7,8,9-Tetrahydro-5-methyl-8-propyl-3-methoxy- 10-methylene-5,8-methano-5 l;l-benzocycloheptene- 7-one was obtained in similar fashion and recrystallized from ethanol; m.p. 118.5-1 19.5C.; )t f s 5.73 1. (five-membered ring ketone), 6.0a C=CH NMR (CDCl;,) exhibited the following chemical shifts 80.99 (t,31-1,(CH C1:1 81.69 (s, 3H), BC- Cfl 83.77 (s, 3H, -OCE), 84.91 and 5.09 (singlets, 2H for C=CH Mass spectrum showed the following major fragme t-ions m/e 270 (M), 255 (base), 241, 227, 213, 199,185, 171.

Other compounds preparable by the above procedure include 6,7,8,9-tetrahydr0-8-methyl-5-ethyl3- methoxy-10-methy1ene-5,S-methano-Sfl-benzocycloheptene-7-one and 6,7,8,9-tetrahydro-5,8-diethyl-3- methoxy-lO-methylene'5,8-methano-5 l;l-benzocycloheptene-7-one.

EXAMPLE l2 6,7,8,9-Tetrahydro-5 ,8, l 0-trimethyl-3-methoxy-5 ,8- methano-SgH-benzocycloheptene-7-one PROCEDURE A A solution of 22.4 g. of 6,7,8,9-tetrahydro-5,8- dimethyl-3-methoxy-10-methylene-S,8-methano-5l 1 benzocycloheptene-7-one in 350 m1. of ethanol was catalytically reduced over 5 g. of prehydrogenated Pd/C catalyst at atmospheric pressure. (Other catalysts e.g. Pt, Ni, were also useful to hydrogenate the exomethylene group). After the hydrogenation had been completed, the catalyst was separated by filtration, and the reaction mixture was evaporated to a colorless syrup.

The crude reaction mixture was purified by distillation at 125C./0.0l mm. Hg.; A1,m ""=5.73,u(ketone), and a 3:2 mixture of the cisand trans- C lC Me stereoisomers of 6,7,8,9-tetrahydro-5,8,l0- trimethyl-3-methoxy-5,8-methano-5fl-benzocycloheptenJ-one was obtained in high yield. NMR spectrum of the C /C -Me' cis isomer exhibited chemical shifts at 80.84 (d, 3H; J=7 cps), 81.07 (s, 3H), 81.47 (s, 3H), 83.77 (s, 3H). The NMR spectrum of C /C Me trans isomer possessed chemical shifts at 81.00 (d, 3H; J=7 cps), 81.12 (s, 3H), 81.51 (s, SH), 8377 (s, 3H).

Analysis for C H O- 244.32 requires: C, 78.65; H, 8.25%. found: C, 78.93; H, 8.60%.

Following the above procedure, but substituting for 6,7,8,9-tetrahydro-5 ,8-dimethyl-3-methoxy l 0 methylene-5,8-methano-5fl-benzocycloheptene-7-one the appropriate 6,7,8,9-tetrahydro-5,8-dialkyl-3- methoxy-10methylene-5 ,S-methano-Sli-benzocycloheptene-7-one, one can obtain 6,7,8,9-tetrahydro- 5,10-dimethyl-8-ethyl-3-methoxy-5,S-methano-Sflbenzocycloheptene-7-one; b.p.=l lOC./0.005 mm. Hg.; )t,,,,,f"'a 5.80p.(ketone). NMR spectrum of the C lC -Me cis isomer (CDCl exhibited chemical shifts at 80.83 (t, 3H), 80.81 (d, 3H; J=7 cps), 81.52 (s, 3H), 83.76 (s, 3H). The NMR spectrum of the C,-,/C Me trans isomer (CDClpossessed chemical shifts at 81.00 (d, 3H; J=7 cps), 81.52 (s, 31-1), 83.76 (s, 3H).

Reduction of 6,7,8,9-tetrahydro-5-methyl-8-ethyl-3- methoxy- 1 O-methylene-S ,8-methano-5fi-benzocycloheptene-7-one with Pd-C (10%) catalyst led to a 2:3 mixture of cisand trans C /C Me-stereoisomers.

Reduction with PtO catalyst provided a 4:1 mixture of the cisand trans-diastereoisomers.

Mass spectrum showed the following major fragment ions: m/e 258 (M base), 243, 229, 215, 201, 187 and 175.

Analysis for C H O 258.35 requires: C, 79.03; H, 8.58%. found: C, 79.03; H, 8.84%.

6,7,8,9-Tetrahydro-5,10-dimethyl-8-propyl-3- methoxy-S,8-methano-5fl-benzocycloheptene-7-one was prepared in similar fashion and was isolated after recrystallization from hexene; m.p. 5l55C. Glc analysis on Se-3O column showed that the ratio of the axial and equatorial diastereoisomer is 91 :9. )t a 5.75pt (five-membered ring ketone); NMR spectrum (CDCl showed no chemical shift for the vinyl protons. A triplet for the CH group of the propyl sidechain and the two sets of doublets for the axial and equatorial C CH protons were not completely resolved. However, the C =,CH;, protons of the two diastereoisomers exhibited two s inglets corresponding to the methyl protons at 81.53 (s;CCH and 81.48 (s, EC-Cl-b), respectively. Mass spectrum possessed the following major fragment-ions m/e 272 (m 257, 243, 229, 215, 201, 199, 1187, (base).

Analysis for C,,,H O 272.37 requires: C, 79.37, H, 8.88%. found: C, 79.60, H, 8.91%.

Other compounds preparable by following the above procedure include 6,7,8,9-tetrahydro-IO-methyl-S- ethyl-8-n-propyl-3methoxy-S,8-methano-5fl-benzocyclohepteneJ-one, 6,7,8,9tetrahydro-8.l-dimethyl-5- ethyl-3-methoxy-5,8methano-Sfl-benzocycloheptene- 7-one and 6,7,8,9-tetrahydro-l0-methyl-5,8-diethyl-3- methoxy-S,8 methanol-l-benzocycloheptene-7one.

EXAMPLE l3 6,7,8 ,9-Tetrahydro-5 ,8-dimethyl-3-methoxy-7- (tetrahydro-Z-pyranyloxy)- l O-hydroxymethyl-S ,8-

methano-Sfl-benzocycloheptene A solution of 26 ml. of 1 molar diborane in tetrahydrofuran was slowly dropped into a solution of 17.3 g. of 6.7.8.9-tetrahydro-5.8-dimethyl-3-mcthoxy-7- (tetrahydro-2-pyranyloxy)-l0-methylene-5,8- methano-Sfl-benzocycloheptene dissolved in 50 ml. of dry tetrahydrofuran held between 0 and C. After the addition had been completed, the reaction mixture was stirred at room temperature for about 1 hour and then decomposed with ice. The mixture was next treated below +18C. with ml. of 10% sodium hydroxide and 10 ml. of H 0 The consequent reaction mixture was stirred at room temperature for about 3 hours, and was then exhaustively extracted with chloroform. Evaporation of the combined chloroform extracts to dryness gave crude 6,7,8,9-tetrahydro-5,8- dimethyl-3-methoxy-7-(tetrahydro-Z-pyranyloxy l 0- hydroxymethyl-S,8methano-Sfl-benzocycloheptene in practically quantitative yield; k 2.95;; (very strongOH); there was no absorption band at 6.07;; for the exomethylene group.

Following the above procedure, but substituting for 6,7,8,9-tetrahydro-5,8-dimethyl-3-methoxy-7- (tetrahydro-Z-pyranyloxy)-l0-methylene-5,8- methano-SE-benzocycloheptene an appropriate 6,7,8,- 9-tetrahydro-5,8-dialkyi-3-methoxy-7-(tetrahydro-2 pyranyloxy)-lO-methylene-S,8-methano-5fibenzocycloheptene, one can obtain 6,7,8,9-tetrahydro- 5-methyl-8-n-propyl-7-( tetrahydro-Z-pyranyloxy l 0- hydroxymethyl-S,8methano-Sfl-benzocycloheptene, 6,7,8,9-tetrahydro-5methyl-S-ethyl3-methoxy-7- (tetrahydro-2-pyranyloxy)-10-hydroxymethyl-5,8- methano-Ski-benzocycloheptene, 6.7.8.9-tetrahydr0-8- methyl-5-ethyl-3-methoxy-7-(tetrahydro-2- pyranyloxy)-lO-hydroxymethyl-S,8-methano-5flbenzocycloheptene and 6,7,8,9-tetrahydro-5,8-diethyl- 3-methoxy-7-(tetrahydro-Z-pyranyloxy)-10- hydroxymethyl-S,S-methano-Sfl-benzocycloheptene.

EXAMPLE l4 6,7,8,9-Tetrahydro-5 ,8-dimethyl-3-methoxy-7- (tetrahydro-2-pyranyloxy l O-tosyloxymethyl-S ,8- methanoSfl-benzocycloheptene A solution of 2.0 g. of 6,7,8,9-tetrahydro-5,8- dimethyl-3-methoxy-7-(tetrahydro-Z-pyranyloxy)- 10- hydroxymethyl-S,S-methano-Sfl-benzocycloheptene in 30 ml. of cold pyridine was treated with 1.2 g. of ptoluenesulfonylchloride. The reaction mixture was stored in the cold for 24 hours, and was poured onto ice. The resulting mixture was diluted with 10% hydrochloric acid. The slightly acidic solution was extracted with ether. Evaporated of the ether therefrom yielded 6,7,8,9-tetrahydro-5,8-dimethyl-3-methoxy-7- I (tetrahydro-2-pyranyloxy)-lO-tosyloxymethyl-5,8- methano-Sfl-benzocycloheptene; A 3.47;;v (very strong CH), 7.37 and 850p. (SO and there was no band for OH absorption.

Following the above procedure. but substituting for 6,7,8,9-tctrahydro-5,8-dimethyl-3-methoxy-7- (tctrahydro-Z-pyranyloxy)-lO-hydroxymethyl-5,8- methano-Sfl-benzocycloheptene an appropriate 6,7,8,- 9-tetrahydro-5,8-dialkyl-3-methoxy-7-(tetrahydro-Z- pyranyloxy)-l0-hydroxymethyl-5.8-methano-5flbenzocycloheptene, one can obtain 6,7,8,9-tetrahydro- 5-mcthyl-8-ethyl-3-methoxy-7(tetrahydro-Z- pyranyloxy )-l 0-tosyloxymethyl-5 ,8-methano-5 H- benzocycloheptene; 6,7,8,9-tetrahydro-5-mcthyl-8- propyl-3-methoxy-7-(tetrahydro-Z-pyranyloxy)-l0- tosyloxymethyl-S,8methano-Sflbenzocycloheptene and 6,7,8,9-tetrahydro-5,8-diethyl-3-methoxy-7- (tetrahydro-Z-pyranyloxy)- l O-tosyloxymethyl-5.8- methano-Sfl-bcnzocycloheptene.

EXAMPLE l5 6,7,8 ,9-Tetrahydro-5 ,8, l O-trimethyl'3-methoxy-5 8- methano-Sfl-benZocycloheptcnc-7ol A solution of 24.4 g. of 6,7,8,9-tetrahydro5,8- dimethyl-3-methoxy-7-(tetrahydro-Zpyranyloxy)- l 0- tosyloxymethyl-S,8methano-Sfl-benzocycloheptenc in 200 ml. of dry tetrahydrofuran was slowly introduced into a slurry 0f5 g. of LiAll-l in ml. of dry tetrahydrofuran. The resulting mixture was refluxed for 16 hours. The reaction mixture was decomposed with an ice-water mixture followed by 1072 hydrochloric acid which treatment also served to hydrolyze the tetrahydropyranyl-ether group. The reaction mixture was extracted with ether. Evaporation of the ether solvent gave a practically quantitative yield of crude 5,8,10- trimethyl-5,S-methano-Sfl-benzocycloheptene7-ol; )t 2.98;; (very strong OH).

Following the above procedure, but substituting for 6,7,8,9-tetrahydro-5,8-dimethyl-3-methoxy-7- (tetrahydro-Z-pyranyloxy l O-tosyloxymethyl-S ,8- methano-Sfl-benzocycloheptene an appropriate 6,7,8,- 9-tetrahydro-5,8-dialkyl-3-methoxy-7-(tetrahydro2- pyranyloxy)-10-tosyloxymethyl-S,S-methano-Sflbenzocycloheptene, one can obtain 6,7,8,9-tetrahydro- 5,lO-dimethyl-3methoxy-8-n-propyl-5,8-methano-5flbenzocycloheptene-7-ol, 6,7,8,9-tetrahydro-5,10- dimethyl-8-ethyl3-methoxy-5,S-methano-Sflbenzocycloheptene-7-ol, 6,7,8,9-tetrahydro-8,10- dimethyl5-ethyl-3-methoxy-5,8-methano-5 l;l benzocycloheptene-7-ol and 6,7,8,9-tetrahydro-l0- methyl-5,8-diethyl-3-methoxy-5,8-methano-5flbenzocycloheptene-7-ol.

EXAMPLE l6 6,7,8,9-Tetrahydro-5,8,10-trimethyl-3-methoxy-5,8- methano-5fl-benzocycloheptene7-one PROCEDURE B A solution of 16.0 g. of 6,7,8,9-tetrahydro-5,8, l0- trimethyl-3-methoxy-5,8-methano-5fl-benzocycloheptene-7-ol in 100 ml. of pyridine was slowly added to a slurry of 13.0 g. of CrO in mi. of pyridine. The reaction mixture was kept at room temperature with stirring for an additional 16 hours. The reaction mixture was filtered, the filtrate was evaporated to a dark syrup which was dissolved in ether, and the ether solution extracted with 10% hydrochloric acid. Evaporation of the ethereal solution yielded crude 6,7,8,9-tetrahydro- 5,8,l0-trimethyl-3-mcthoxy-5,S-methanodfl-benzocycloheptene-7-one in practically quantitative yield. Distillation of an aliquot of the syrup at l30-135C./0.01 mm. Hg. gave the pure (I /C -trans-stereoisomer of 6,- 7,8,9-tetrahydro-5.8,l0-trimethyl-3-methoxy5,8-

melted at 144.5145.5C.; A

methano-Sfi-benzocycloheptene-7-one. NMR spectrum was identical with the sample obtained by a different route in Example 12 and exhibited chemical shifts for the C lC -trans-dimethyl groups at 81.03 ppm. (d, J=7 cps; C 81.12 (s, C,,-Q1 81.51 ppm. (singlet, for C --CH and 83.77 (s; C C l -l Following the above procedure, but substituting for 6,7,8,9-tetrahydro-5,8,10-trimethyl-3-methoxy-5,8- methano-SH-benzocyclohepteneJ-ol, an appropriate 6,7,8,9-tetrahydro-5,8, 10-tria1kyl-3-methoxy*5,8- methano-SH-benzocyclohepteneJ-ol, one can obtain 6,7,8,9-tetrahydro-5,10-dimethyl-8-ethyl-3-methoxy- 5,8-methano-Sfl-benzocycloheptene-7-one,

(from pentane), 6,7,8,9-tetrahydro- 5,10-dimethyl-8-n-propyl-3-methoxy-5,8-methano5flbenzocycloheptene-7-one; m.p. 1 18.5-119.5C. (ethanol) 6,7,8,9-tetrahydro-8,10-dimethy1-5-ethyl-3- methoxy-S,8-methano-5 l;l -benzocycloheptene-7-one and 6,7,8 ,9-tetrahydro-10-methyl-5 ,8-diethyl-3- methoxy-S,8-methano-Sfl-benzocyclohepteneJ-one.

EXAMPLE 17 6,7,8,9-Tetrahydro-5 ,8, l -trimethyl-3-methoxy-5,8- methano-fl-benzocycloheptene-7-one oxime A solution of 22.7 g. of 6,7,8,9-tetrahydro-5,8,10- trimethyl-3-methoxy-5,8-methano-5ll -benzocycloheptene-7-one in 60 ml. of methanol containing a 1.5 mol equivalent amount of hydroxylamine acetate was refluxed for about 5 hours. The reaction mixture was evaporated to dryness, and the residue extracted with ether. The dried ethereal layer gave 23.0 g. of a gum on evaporation to dryness. Recrystallization of the gum from ether-hexane yielded the pure oxime which 3.05]J,(OH). NMR spepctrum exhibited chemical shifts for its C CH -protons at 80.75 (d, .l=7cps), which indicates a C /c -cis-dimethyl configuration. Mass spectrum exhibited the following major fragment ions: m/e 259 (M), 224, 242 (base), 201.

Analysis forC -H NOZ 259.33: requires: C, 74. 10; H, 8.16; N, 5.40%. found: C, 73.94; H, 7.96; N, 5.23%.

A similar procedure starting from the trans-C /C dimethyl diastereoisomer from Example 16, yielded the isomeric oxime, m.p.=190-193C. NMR spectrum verified the transstereochemistry of the C /C -methy1 groups possessing chemical shifts for its C -methyl protons at 80.94 ((1, 3H; J=7 cps).

Following the above procedure but substituting for 6,7,8,9-tetrahydro-5 ,8,10-trimethyl-3-methoxy-5 ,8- methano-Sfl-benzocyc1oheptene-7-one an appropriate 6,7,8 ,9-tetrahydro-5 ,8,10-trialkyl-3-methoxy-5 ,8- methano-Sfl-benzocyclohepteneJ-one, one can obtain 6,7,8,9-tetrahydro-5 ,10-dimethyl-8-ethyl-3-methoxy- 5,8-methano-5H-benzocycloheptene-7-one oxime. The trans-C /C -Me isomer melted at 195.5196.5C.; )t tt 3.0;.t(broadOH); 100 MHz NMR spectrum in CDC1 showed chemical shifts at 80.96 (t, 3H), 81.41 (s, 3H), 81.69 (q, 2H), 82.04 (q, 1H), 83.77 (s, 3H). The cis-C /C -Me isomer melted at 126.5-132.5C. NMR spectrum indicated a mixture of 87% cisand 13% transisomers. NMR spectrum of the pure cisisomer exhibited chemical shifts at 80.74 (t, 3H), 81.45 (s, 3H) and 83.75 (s. 3H).

Mass spectrum of the oxime showed the following fragment peaks: m/e 273 (M*), 258, 256, 215 (base), 187, 186.

Analysis forC I-1l NO ,273.36: requires: C,74.69, H, 8.48; N, 5.12%. found: C, 74.76; H, 8.64; N, 5.30%.

6,7,8,9-Tetrahydro-5,10-dimethyl-8-n-propyl-3- methoxy-5,8-methanofl-benzocycloheptene-7one oxime was prepared in similar fashion; m.p. 158161C. (from benzene-heptane); f' a 2.80, 3.00;]. (-OH). Mass spectrum possessed the following major fragment-ions m/e 287 (M*), 272, 229 (base), 200, 187, 172.

Analysis for C N NO, 287.39:

requires: C, 75.22; H, 8.77; N, 4.87%. found: C, 75.41; H, 8.57; N, 4.86%.

6,7,8,9-Tetrahydro-8,lO-dimethyl-5-ethyl-3- methoxy-S,8-methano-5 l;l-benzocycloheptene-7-one oxime and 6,7,8,9-tetrahydro-l0-methyl-5,8-diethyl-3- methoxy-S,8-methano5fl-benzocycloheptene-7-oneoxime can be obtained in similar fashion.

EXAMPLE l8 1,2,3,4,5,6-Hexahydro-2,6-1 l-trimethyl-8-methoxy- 2,6-methano-3-benzazocine-4-one An ice-cold solution of 25.9 g. of the cis-C /C dimethyl diastereoisomer of 6,7,8,9-tetrahydro-5,8,10- trimethyl-3-methoxy-5,8-methano-51-l -benzocycloheptene-7-one oxime in 500 ml. of pyridine was treated with 19.0 g. p-tosylchloride and the resulting mixture stirred at 0C. for 16 hours. The mixture was allowed to warm up to room temperature at which temperature it was maintained for 24 hours. The reaction mixture was evaporated in vacuo at 30C. bath temperature to a syrup which was dissolved in benzene. The benzene solution was extracted with 10% hydrochloric acid and water and dried. Evaporation of the benzene yielded about 3540% of the cis-C /C -Me isomer lactam. Recrystallization from ethylacetate hexane yielded purified cis lactam; m.p.=200201.5C.; A 3.20;. (sharp NH); 6.03,u.(strongCO--NH). NMR spectrum in DMSO-d,, exhibited the diamagnetically shifted C -methyl protons at 80.79 (cl, 3H).

Mass spectrum showed the following fragmentation: m/e 259 (M), 244, 200, 161, 138.

Analysis for C H NO 259.33: requires: C, 74.10; H, 8.16; N, 5.40%. found: C, 73,87; H, 8.37; N, 5.38%.

Similar Beckmann rearrangement of the C /C transdimethyl oxime diastereoisomer yielded the c /C- -transdimethyl diastereoisomer of 1,2,14,5-

hexahydro-2,6, 1 1-trimethyl-8-methoxy-2,6-methano- 3-benzazocine-4-one m.p.=209.5210C. NMR spectrum verified the trans-diequatorially oriented C /C methyl groups by exhibiting the C -methyl protons at 80.96 (d, 3H) in DMSO-d,; solution.

Following the above procedure, but substituting for 6,7 ,8 ,9-tetrahydro-5,8, 1 0-trimethyl-3 -methoxy5 ,8- methano-5fl-benzocycloheptene 7-one oxime an appropriate 6,7,8 ,9-tetrahydro-5 ,8, 10-trialkyl-3- methoxy-S,8-methano-5lj-benzocycloheptene-7-one oxime, one can obtain 1,2,3,4,5,6hexahydro-6,l 1- dimethyl-2-ethyl-8-methoxy-2,6-methano-3- benzazocine-4-one. The cis-c /C -methyl diastereoisomer lactam was recrystallized from CHCl -ether; m.p.=164167C. 3.20,u.(N1-1), 6.05,u.(CONH).

Mass spectrum possessed a weak molecular ion: 273 (WP) and the following major fragment ions: m/e 258 (base), 215, 214,187 and 175.

Analysis for C H NO 273.36: requires: C, 74.69; H, 8.48; N, 5.12%. found: C, 74.46; H, 8.21; N, 5.03%.

The trans-C /C methyl stereoisomer lactam melted at 285286.

Similar Beckmann-rearrangement of 6,7,8,9- tetrahydro-S ,10-dimethyl-8-n-propyl-3-methoxy-5,8-

methano-Sfl-benzocycloheptene-7-one oxime provided 1,2,3,4,5,6-hexahydro-trans-6,1 l-dimethyl-Z-npropyl-8-methoxy-2,6-methano-3-benzazocine-4-one, m.p. 25926lC. (from ethanol) and the cisdiastereoisomer lactam, m.p. 159166C. (from ethyl acetate-hexane). Both racemate pairs showed a closely related IR spectra; k f 2.91;; (NH), 6.03 (NHCO). Mass spectrum showed the following major fragment-ions m/e 287 (M*), 272 (base), 244, 230, 188, 166.

Analysis for C H NO 287.39: requires: C, 75.22; H, 8.77 N, 4.87%. found: C, 75.34; H, 8.68; N, 4.59%.

1,2,3,4,5,6-Hexahydro2,l l-dimethyl-6-ethyl-8- methoxy-2,6-methano3-benzazocine-4-one, 1,2,3,4,5- ,-hexahydro-l l-methyl-6-ethyl-2npropyl-8 methoxy-2,6-methano-3-benzaZocine-4-one and 1,2,3,- 4,5,6-hexahydro-l 1-methyl-2,6-diethyl-8-methoxy- 2,6-methano-3-benza2ocine-4-one can be prepared in similar fashion.

EXAMPLE l9 l,2,3,4,5,6-Hexahydro-2,6,l l-trimethyl-8-methoxy- 2,6-methano-3-benzazocine 17.0 g. of l,2,3,4,5,6-hexahydro-2,6,l1-trimethyl-8- methoxy-2,6-methano-3-benzazocine-4-one was added in small portions to a slurry of 10.0 g. lithium aluminumhydride in 700 ml. of dry tetrahydrofuran. The resulting mixture was refluxed for about 14 days. After conventional workup, crude l,2,3,4,5,6-hexahydro- 2,6,1 1-trimethyl-8-methoxy2,6-methano-3- benzazocine was obtained. The crude amine was dissolved in ether, and the ether solution treated with dry ethereal hydrochloric acid. l,2,3,4,5,6-Hexahydro- 2,6,1 l-trimethyl-8-methoxy-2,6-methano-3- benzazocine hydrochloride thus formed was recrystallized from ethanol; m.p. 272-273C. (dec.); x,,,,,,'" 3.54.0u(secondary amine salt.) 100 MHz NMR spectrum of the trans-C /c -methyl diastereoisomer obtained above in CDCl /D o/KOD solution exhibited chemical shifts at 81.06 (d, 3H; C -equatorial methyl protons), 61.18 (s, 3H) 81.35 (s, 3H), 83.78 (s, 3H).

100 MHZ NMR spectrum of the cis-C /c -methyl isomeric amine obtained in similar fashion in CDCl /D O/KOD showed the diamagnetically shifted doublet for its C -methyl protons at 60.80 ((1, 3H) and chemical shifts at 81.14 (s, 3H), 1.43 (s, 3H), 83.78 (s, 3H).

Mass spectrum of the amine possessed the following fragment ion peaks: m/e 245 (M*), 230 (base), 216, 187, 174, 161.

Analysis for C H NOCI, 281.80: requires: C, 68.19; H, 8.58; N, 4.97%. found: C, 67.99, H, 849; N, 4.91%.

Following the above procedure, but substituting for 1,2,3,4,5,6-hexahydro-2,6,1 l-trimethyl-8-meth0xy- 2,6-methano-3-benzazocine-4-one an appropriate 1,2,- 3,4,5,6-hexahydro-2,6,l l-trialky-8-methoxy-2,6- methano-3-benzazocine-4-one, one can obtain 1,2,3,4- ,5,6-hexahydro-6,l l-dimethyl-2-ethyl-8-mcthoxy-2,6- methano-3-benzazocine, the hydrochloride salt of which melted at 284286C.; k f 'a 3.55-4.0a (secondary amine salt).

Analysis for C H NOCl, 295.83: requires: C, 69.02; H, 8.86; N, 4.73%. found: C, 68.81; H, 8.67; N, 4.70%. l,2,3,4,5,6-Hexahydro-6,l l-dimethyl-2-n-propyl-8- methoxy-Z,6-methano-3-benzazocine was prepared in similar fashion and isolated as its hydrobromide salt;

m.p. 238.5240.5C.

20 Similarly, l,2,3,4,5,6-hexahydro-2,l l-dimethyl-6- ethyl8-methoxy-2,6-methano-3-henzazocine and 1,2,- 3,4,5,6-hexahydro-l 1-methyl-2.6-diethyl-8-methoxy- 2,6-methano-3-benzazocine were prepared.

EXAMPLE 20 1.2,3,4,5,6-Hexahydro-2,6,l l-trimethyl-2,6-mcthano- 3-benzazocine-8ol Ten grams of l,2,3,4,5,6-hexahydro-2,6,l ltrimcthyl-8-methoxy-2,6methano-3-benzazocine hydrochloride were melted in an oil bath with 40 g. of pyridinium hydrochloride at a temperature in the range l70l85C. for 16 hours. The reaction mixture was cooled and dissolved in water. The aqueous solution was made alkaline by the addition of, ammonium hydroxide at 0C., and the base insoluble material extracted into chloroform. The chloroform layer was separated and evaporated to dryness. The resulting residue was triturated with ether. l,2,3,4,5,6-hexahydro- 2,6,1l-trimethyl-2,6-methano-3-benzazocine-8-ol thus obtained crystallized and was separated by filtration; m.p. 235237C. A,,,,,," 3.05 4.0p.; NMR (DMSO-(lu) 80.70 (d, 3H), 81.07 (s, 3H). 51.28 (s, 3H).

Mass spectrum exhibited the following fragmentation pattern: m/e 231 (m*), 216 (base), 202, 186, 173, 160, 145, 124.

Analysis for C H NO. 231.34: requires: C, 77.88; H, 9.15; N, 6.05%. found: C, 77.54; H, 8.96; N, 5,86%.

Following the above procedure, but substituting for l,2,3,4,5,6-hexahydro-2,6,l l-trimethyl-8-methoxy- 2,6-methano-3benzazocine an appropriate l,2,3,4,5,- 6-hexahydro-2,6,l l-trialkyl-8-methoxy-2,6-methano- 3-benzazocine, one can obtain l,2,3,4,5,6-hexahydro- 6,1 1-dimethyl-2ethyl-2,6-methano-3-benzazoeine-8- ol; m.p.=238243C. (from ethanol) and 1,2,3,4,5,6- hexahydro-6,l 1-dimethyl-2-n-propyl-2,6-methano-3- benzazocine-8-ol; m.p. 1798lC (isopropanol).

1,2,3,4,5,6-Hexahydro-2,l l-dimethyl-6-ethyl-2,6- methano-3-benzazocine8-ol and l,2,3,4,5 ,6- hexahydro-l l-methyl-2,6-diethyl-2,6-methano-3-benzazocine-S-ol can also can be obtained by the above procedure.

EXAMPLE 21 1 ,2,3,4,5,6-Hexahydro-3-(Bphenethyl)-2,6,l ltrimethyl-2,6-methano-3-benzazocine-8-ol A suspension of 6.01 g. of 1,2,3,4,5,6-hexahydro- 2,6,1l-trimethyl-2,o-methano-3-benzazocine-8-ol in a mixture of 260 ml. of CH CI and 45 ml. Et N was slowly treated with 12.0 g. (3 mole eq.) of freshly distilled phenylacetychloride and the resulting mixture refluxed for 16 hours. The yellow solution thus obtained was cooled and extracted by cold-dilute HCl. The organic layer was separated, dried and filtered. Evaporation of the solvent left the N,O-diacylated product as a yellow gum; A 5.75)\(OCOCH -Ph) and 5.95( NCOCH -Ph).

The crude N,O-diacyl benzazocine thus prepared was reduced with 2,0 g. of LiAlH, in 350 ml. of refluxing THF. The pooled solution was diluted with 300 ml. of ether and carefully decomposed by adding an ice-water mixture. The solution was filtered to remove inorganic salts. The filtrate was dried and the solvents removed by evaporation. The residue was chromatographed over neutral alumina, The free base was eluted with chloroform. The corresponding hydrochloride salt was prepared: m.p.=l60l69C.

A mass spectrogram ofthe hydrochloride salt did not show the expected molecular ion (M 335), Apparently, a benzyl group (M-91 was lost, giving rise to the following fragmentation pattern: m/e 187, 159, 141, 129, 105, 1103, 91

Analysis calc. for C H NOCI: C, 74.20; H, 8.12; N, 3.76. Found: C, 74.02; H, 8.14; N, 3.64.

Following the above procedure but substituting for 1,2,3,4,5,6-hexahydro2,6,l l-trimethyl-2,6-methano- 3-benzazocin-8-ol, 1,2,3,4,5 ,6-hexahydro-6, 1 1- dimethyl-2ethyl-2,6'methano-3-benzazocin-8- ol,1,2,3,4,5,6-hexahydro-3-(B-phenethyl)-6,1 1- dimethyl-2-ethyl-2,6-methano-3-benzazcin-8-ol was prepared and crystallized as the hydrobromide salt from ethanol/ether: m.p.=183-5C.; )t,,,,,,"" 3.40, 3.48, 3.703.80;tt(salt). Mass spectrograph showed no molecular ion at M 349. The fragmentation pattern shows a series of ions at m/e 348, 334 and 320.

Analysis calc. for C l-l NOBr: C, 66.97; H, 7.49; N, 3.25. Found: C, 67.06; H, 7.37; N, 3.38.

The tartrate salt of the above amine base was also prepared:

Analysis calc. for C H NO C, 67.31; H, 7.47; N, 2.80. Found: C, 67.52; H, 7.45; N, 3.09.

EXAMPLE 22 1,2,3,4,5,6-l-lexahydro-3-(BphenethyI)-6,1 1- dimethyl-2-ethyl-2,6-methano-3-benzazocine-8-ol An alternate procedure to Example 21 was carried out as follows:

A mixture of 7.15 g. of 1,2,3,4,5,6-hexahydro-3-(B- phenethyl)-6,l l-dimethyl-2-ethyl-8-methoxy-2,6-

methane-3-benzazocine-hydrochloride prepared by the procedure of Example 23 and 35 g pyridiniumhydrochloride was heated at 170C. for 6 hours. The cooled reaction mixture was dissolved in water, and the water solution neutralized with diluted NH Ol-l and extracted with chloroform. The dark chloroform solution was separated and evaporated in vacuo. The resulting residue was triturated with pentane. After several triturations with pentane, a solid foam remained with the chromatographed over neutral alumina using benzene as the eluant. l,2,3,4,5,6-Hexahydro-3-(B-phenethyl)- 6,l 1-dimethyl-2-ethyl-2,6-methano-3-benzazocine-8- 01 thus prepared was converted to the hydrobromide salt in dry ether m.p. 183l85(dec) after recrystallization from an ethanol/ether mixture. The product was identical in all respects with the sample described in Example 21.

EXAMPLE 23 1,2,3,4,5,6-Hexahydro-3-(B-phenethyl)-2,6,1 1- trimethyl'8-methoxy-2,6-methano-3-benzazocine To a mixture of 2.79 g. of l,2,3,4,5,6hexahydro- 2,6,1 1-trimethyl-8-methoxy-2,6-methano-3- benzazocine in 150 ml. of CH CI and 18 ml. of Et N was slowly added 3.0 g. of phenacetylchloride. The reaction mixture was refluxed for 16 hours, cooled and then extracted with cold dilute hydrochloric acid. The

organic layer was separated and the solvent evaporated to leave a gum film 6.1a, NCO comprising the N-phenacetyl derivative which was reduced with 1.0 g. LiAlH, by the procedure of Example 21. 1,- 2,3,4,5,6-Hexahydro-3-(B-phenethyl)-2,6,1 1-

trimethyl-S-methoxy-Z,6-methano 3-benzazocine was eluted with benzene and transformed into the corre sponding hydrochloride salt. k f a 4.0-41p.(tertiary amine salt).

The mass spectrum did not show the molecular ion (M 343), but had the following fragmentation pattern m/e 258. 245, 230, 201. 60 MHZ n.m.r. spectrum in CDCl exhibited the protons of the phenyl group at 87.28 (s), as well as the protons of the trisubstituted aromatic nucleus at 57.0 (m).

Following the above procedure, but substituting the secondary amine benzazocine component with an equimolar amount of 1,2,3,4,5,6-hexahydro-6,1 l dimethyl- 2ethyl-8-methoxy-2,6-methano3-benzazocine, one obtains 1,2,3,4,5,6-hexahydro-34B'phenethyl)-6,l 1- dimethyl-2-ethyl-8methoxy-2,6-methano-3- benzazocine which was isolated in hydrochloride salt form; m.p. 208-209C. (dec.), (ethylacetate/ether). h a 407p. (broad, tertiary amine salt). 60 MHZ n.m.r. spectrum in CDCL, exhibited chemical shifts at 8086 ((1, 31-1), 63.81 (s, 3H), 86.91 (m, 3H) trisubstituted aromatic protons), 57.29 (s, 5H; -C H,,).

Mass spectrum did not show the molecular ion (M 363). The following major fragment ions were observed: m/e 272, 243, 229, 215, 187 and 173.

Analysis for C H NO.Cl, 400.01 requires: C, 75.07; H, 8.57; N, 3.50%. Found: C, 75.00; H, 8.82; N, 3.49%.

EXAMPLE 24 PREPARATION OF SALTS Salts of the free bases of this invention, other than the hydrochloride or hydrobromide salts whose preparation is illustrated in the above examples, are prepared by dissolving the free base in ether and adding an equivalent of a suitable non-toxic acid, also in ether. The salts thus formed, as for example the sulfate and phosphate salts, are insoluble in ether and can be isolated by filtration. Alternatively, the amine base can be dissolved in ethanol and an equivalent of the acid added as an ethanolic solution. In this instance, since a majority of the salts thus formed are soluble in the reaction mixture, they are isolated by addition of ether orby evaporation of the solvent in vacuo. Purification is usually by recrystallization. Salts which can be formed by the above procedure include the sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, maleate, fumarate succinate, tartrate, citrate, lactate, benzoate, methane sulfonate and p-toluene sulfonate salts of the novel benzazocines of this invention.

As previously stated, the compounds of this invention are analgetics. For example, l,2,3,4,5,6-hexahydro- 2,6,1 l-trimethyl3-(B-phenethyl)2,6-methano-3-benzazocine-8-ol is a pure analgetic, more powerful than pentazocine but without significant analgetic antagonist activity. The corresponding 8-methyl ether is also analgetically active, though not as active as the benzazocine-S-ol. The higher homologues, the 1,2,3,4,5,6-hexahydro-2-ethyl (or 2-propyl)-6,1l dimethyl-3-substituted-2,6-methano-3-benzazocine-8- 01s and the corresponding 8-methoxy ethers are also active analgetics, with those derivatives having a free phenolic group at 8 being particularly active.

The compounds of this invention may be administered to mammals to produce analgesia either parenterally or orally. Pharmaceutical formulations for the administration of the compounds of this invention to mammals include the use of solid pharmaceutical forms such as tablets and pulvules or in liquid forms including solutions, suspensions or emulsions. Suitable liquid and solid carriers including water, gelatin, lactose, starch,

talc, vegetable oils, alcohols. polyalcohols, gums, syrups and the like can be used The pharmaceutical composition in addition to the active principle and carrier, may include auxiliary materials such as coloring or stabilizing agents, or wetting or emulsifying agents. It is, of course, recognized that the carrier as well as any other materials present, must be chemically and physiologically inert with respect to the active principle.

When the pharmaceutical preparation is compounded in the manner suggested above. it will contain an amount of from about l500 mg/ml of the vehicle of the analgesic substance. When so prepared. the novel compounds of this invention may be administered in therapeutic dosages of from about -200 mg/day to a mammal.

I claim:

1. A substituted benzazocine of the formula .alk

R 0 Lee wherein each alk is independently -C alkyl and R is H or alk and pharmaceutically-acceptablc acid additive salts thereofformed with non-toxic acids.

2. A compound according to claim 1, said compound being l2.3,4.5.6-heXahydro-2,6,l l-trimethyL3-(B- phenethyl)-2,o-methan0-3-benzazocine-8-ol.

3. A compound according to claim I, said compound being l,2,3,4.5,6-hexahydro2-ethyl-6.l l-dimethyl-3- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT N0. 5,891,658 DATED 1 June 2h, 1975 INVENTOMS): Stephen I. Sallay flwcwmmdmmenmmmmminwemmw-mamfimpmmtmdmmsmdLflmmPmmt are hereby corrected as shown below: g 1 0f 5 In column 1, lines 15-25, the formula should read In column 2, lines 5T-h5, the formula should read UNITED sTATEs PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 5,891,658

DATED June 21; 1975 |NVENTOR(S) Stephen I.

It is certified that error appears in the aboveare hereby corrected as shown below: Page 2 o Sallay identified patent and that said Letters Patent In column 5, lines B t- +5, the formulas should read @O a1 allyl In columns 5 and t, lines 52-68, the formulas should read a1 allyl OO-alk O 1k alk O V Ia1 allyl UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT No. 5,891,658 DATED June 2h, 1 INVENTOR(S) p n 1- Sallay It is certified that error appears in the above-identified patent and that soid Letters Patent are hereby corrected as shown below: (pa 5 of 5) In column L lines 12-19, the formulas should read VIII In columns 5 and 6, lines 1-17, the formulas should read all:

. alk I c=o m OlHP (CSHS )3 P=CH2 OTHP alk aik alk fi X Xi W oxldatlon UNITED STATES PATENT oFFicE CERTIFICATE OF CORRECTION PATENT NO. ,8 DATED June 21;, 975

INVENTOR(S) Stephen I Sallay It is certified that error appears in the aboveidentified patent and that said Letters Patent are hereby corrected as shown below: (Page of 5 In column 5, lines 50-56, the formula should read A alk -2'.l. s-o o C "I, 2. 3.2 5

In column 12, line 6 "tetrahy-" should read tetrahydro- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT N0. 5,891,658 DATED J 1975 mvrzmorarsr Stephen L s llay It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: pa 5 of 5 In column 2h, lines 1-7, the formula should read Signed and Sealed this sixteenth D3) Of December 1975 [SEAL] A ttest:

RUTH C. MASON C. MARSHALL DANN Atrexting Officer Commissioner uj'lalems and Trademarks 

1. A SUBSTITUTED BENZAZOCINE OF THE FORMULA
 2. A compound according to claim 1, said compound being 1,2,3,4, 5,6-hexahydro-2,6,11-trimethyl-3-( Beta -phenethyl)-2,6-methano-3-benzazocine-8-ol.
 3. A compound according to claim 1, said compound being 1,2,3,4, 5,6-hexahydro-2-ethyl-6,11-dimethyl-3-( Beta -phenethyl)-2,6-methano-3-benzazocine-8-ol. 